Levcromakalim

Levcromakalim and MgGDP activate small conductance ATP-sensitive K+ channels of K+ channel pore 6.1/sulfonylurea receptor 2A in pig detrusor smooth muscle cells: uncoupling of cAMP signal pathways.[Pubmed:18596222]

J Pharmacol Exp Ther. 2008 Oct;327(1):114-23.

Pharmacological studies have suggested the existence of ATP-sensitive K(+) (K(ATP)) channel as a therapeutic target in urinary bladders; however, electrical properties have not yet been shown. Patch-clamp techniques were applied to investigate the properties of K(ATP) channels in pig detrusor cells. In whole-cell configuration, Levcromakalim, a K(ATP) channel opener, induced a long-lasting outward current in a concentration-dependent manner. The current-voltage curve of the Levcromakalim-induced membrane current intersected at approximately -80 mV. This current was abolished by glibenclamide. Intracellular application of 0.1 mM GDP significantly enhanced the Levcromakalim-induced membrane current, whereas cAMP did not. Furthermore, neurotransmitters related to cAMP signaling, such as calcitonin gene-related peptide, vasointestinal peptide, adenosine, and somatostatin, had little effect on the membrane current. In cell-attached configuration, Levcromakalim activated K(+) channels with a unitary conductance of approximately 12 pS. When the patch configuration was changed to inside-out mode, the K(+) channel activity ran down. Subsequent application of 1 mM GDP reactivated the channels. The openings of the approximately 12 pS K(+) channels in the presence of 1 mM GDP was suppressed by ATP and glibenclamide. In reverse transcription-polymerase chain reaction, K(+) channel pore 6.1 and sulfonylurea receptor (SUR)2A were predominant in pig detrusor cells. The 12 pS K(+) channel activated by Levcromakalim in pig detrusor smooth muscle cells is a K(ATP) channel. The predominant expression of SUR2A can account for the lack of effect of neurotransmitters related to cAMP.

Evaluation of the potassium channel activator levcromakalim (BRL38227) on the lipid profile, electrolytes and blood glucose levels of streptozotocin-diabetic rats.[Pubmed:23374501]

J Diabetes. 2013 Mar;5(1):88-94.

BACKGROUND: Levcromakalim is a vasorelaxant used in the management of hypertension in diabetes mellitus. Thus, the effects of Levcromakalim were investigated in streptozotocin (STZ)-diabetic rats. METHODS: Diabetes was induced in Wistar albino rats with a single injection of STZ (60 mg/kg, i.p.) following chronic (4 weeks) treatment with Levcromakalim (75 mug/kg per day). Rats were then divided into the following groups (n = 5 in each group): (i) a normal saline (2 mL/kg)-treated group; (ii) a 5 mg/kg glibenclamide-treated group; (iii) 350 mg/kg metformin-treated group; and (iv) 5, 10, 20 and 40 IU/kg insulin-treated groups. Rats were transferred to metabolic cages and the lipid profile, plasma and urine electrolytes and blood glucose levels were determined 24 h after drug administration. RESULTS: Levcromakalim treatment significantly reduced total cholesterol, low-density lipoprotein (LDL), and triglyceride levels in diabetic rats (all P < 0.05 compared with untreated diabetic rats). In addition, Levcromakalim reduced plasma sodium, bicarbonate, and chloride levels, but increased urinary bicarbonate and chloride levels, in diabetic rats (all P < 0.05 compared with untreated diabetic rats). Levcromakalim significantly inhibited the effects of glibenclamide, metformin, and low-dose (20 IU/kg) insulin treatment in diabetic rats (all P < 0.05). Only 40 IU/kg insulin produced significant reductions in hyperglycemia in Levcromakalim-treated diabetic rats. CONCLUSION: Levcromakalim induced resistance to glibenclamide, metformin, and low-dose insulin treatment in diabetic rats, leading to persistent hyperglycemia. However, reductions in LDL, total cholesterol and triglyceride levels following chronic levcromokalim treatment may decrease the risk of cardiovascular disease in diabetic rats.

Vasorelaxant effect of levcromakalim on isolated umbilical arteries of preeclamptic women.[Pubmed:17123695]

Eur J Obstet Gynecol Reprod Biol. 2007 Oct;134(2):169-73.

OBJECTIVE: Potassium channel openers are revealed to be a new type of antihypertensive drug. We aimed to clarify the effects of Levcromakalim, an ATP-sensitive potassium channel opener, on human isolated umbilical artery (UA) and to compare them with those of nifedipine and magnesium sulphate, which are currently used in the treatment of preeclampsia (PE). STUDY DESIGN: A total of 52 umbilical arteries, isolated immediately after delivery from 27 healthy and 25 preeclamptic pregnant women, were placed into 10-ml organ baths filled with Kreb's solution at physiological pH and temperature. The concentration-dependent relaxations in response to Levcromakalim, nifedipine and magnesium sulphate were compared in vessels precontracted with serotonin (1 micromol/l). RESULTS: The maximal relative relaxation responses (E(max), expressed as percentage of serotonin-induced precontraction) to magnesium sulphate, nifedipine and Levcromakalim in umbilical arteries were identical in the healthy (85.06+/-3.31, 84.80+/-3.01 and 80.37+/-5.32%, respectively) and preeclamptic (77.20+/-5.30, 83.36+/-2.37 and 79.13+/-4.30%, respectively) groups. CONCLUSION: Levcromakalim has a vasodilatory effect on the umbilical artery like magnesium sulphate and nifedipine, and serves as an antihypertensive potential that might be used in the treatment of preeclampsia. However, further experimental and clinical studies are needed to propose that ATP-sensitive potassium channel openers are beneficial drugs in cases of clinical preeclampsia.

The potassium channel opener levcromakalim causes expansive remodelling of experimental vein grafts.[Pubmed:16828441]

J Vasc Surg. 2006 Jul;44(1):159-65.

BACKGROUND: Maintenance of luminal area is essential for the optimal performance of venous bypass grafts. However, injury and response to the arterial circulation evoke vascular remodelling that favors intimal hyperplasia, with luminal encroachment and inward remodelling. Potassium channel-opening drugs reduce tissue workload and peripheral vascular resistance and through these mechanisms could favor outward or expansive remodelling of vein grafts. We tested the hypothesis that Levcromakalim, a potassium channel opener, would enhance expansive remodelling in vein grafts. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in 33 rats with vena cava-to-aorta bypass grafts. Drugs were administered via osmotic pump for 7 days after surgery. Half the cohort had bromodeoxyuridine (BrdU) infused at day 6. Morphometric analysis was conducted of pressure perfusion-fixed grafts harvested at 1 week and 4 weeks. RESULTS: At 1 week, lumen area was similar in both groups (1.82 +/- 0.39 mm(2) placebo vs 1.85 +/- 0.36 mm(2) Levcromakalim), although medial cell density and BrdU staining were significantly increased in the placebo group. At 4 weeks, lumen area was unchanged in the placebo group (1.88 +/- 0.51 mm(2)) but had increased to 2.32 +/- 0.46 mm(2) in the Levcromakalim group (P = .039 vs 1 week), with a very significant reduction in the intimal area (Levcromakalim, 0.06 +/- 0.02 mm(2) vs placebo, 0.33 +/- 0.17 mm(2); P = .001). CONCLUSIONS: Early, short-term treatment with Levcromakalim favors expansive remodelling of experimental vein grafts to mimic the effect of external stenting. This expansive remodelling was associated with a reduction in medial cell proliferation at 1 week. CLINICAL RELEVANCE: Critical limb ischemia can be treated by bypass surgery or angioplasty, but inward remodelling with restenosis is a common problem. There has been little previous experimental work to identify treatments associated with expansive remodelling, which would increase the chances of vessel patency. Here, in a randomized trial, we show that short-term treatment with a potassium channel opener (a class of drug that can be used to treat hypertension) results in strong, expansive remodelling, with increases the lumen area and graft size of experimental vein grafts by >25%.

Potassium channel modulation in rat portal vein by ATP depletion: a comparison with the effects of levcromakalim (BRL 38227).[Pubmed:1467843]

Br J Pharmacol. 1992 Dec;107(4):945-55.

1. The effects of Levcromakalim and of adenosine 5'-triphosphate (ATP) depletion on membrane potential and ionic currents were studied in freshly-dispersed smooth muscle cells of rat portal vein by use of combined voltage- and current-clamp techniques. 2. Levcromakalim (1 microM) induced a glibenclamide-sensitive, non-inactivating K-current (IKCO) and simultaneously inhibited the slow, transient outward, delayed rectifier K-current (ITO). Levcromakalim also hyperpolarized the portal vein cells by approximately 20 mV. 3. Reduction of intracellular ATP by removal of glucose and carboxylic acids from the recording pipette and of glucose from the bath fluid, induced a slowly-developing, non-inactivating and glibenclamide-sensitive K-current (Imet) within 60-300 s after breaking the membrane patch. Imet reached peak amplitude after 300-900 s, remained at a plateau for 200-800 s and then slowly ran down. At the peak of Imet, the cells were hyperpolarized by approximately 20 mV and their input conductance was increased by 42%. 4. At the time of maximum development of Imet, the delayed rectifier current, ITO, was reduced by 48%. 5. In the absence of glucose and carboxylic acids, addition of 1 microM free ATP to the recording pipette almost doubled the magnitude of Imet. At a holding potential of -10 mV, Imet was increased from 124 +/- 11 pA to 228 +/- 54 pA whereas the time-course of development and run-down of Imet was unaffected. 6. During the development and after the run-down of Imet, Levcromakalim (1-10 microM) failed to induce IKCO. 7. Stationary fluctuation analysis of the current noise associated with Imet revealed a unitary conductance of between 10-20 pS in a physiological potassium gradient. A second contaminating current with an underlying unitary conductance of approximately 150 pS remained after Imet had run down. 8. It is concluded that IKCO induced by Levcromakalim and Imet are carried by the same population of relatively small conductance, glibenclamide-sensitive K-channels. The open state of these is increased by procedures designed to lower intracellular ATP concentrations. 9. The simultaneous inhibition of the delayed rectifier current (ITO) by both Levcromakalim and during the development of Imet is highly significant. It suggests that Levcromakalim could modify the interaction of ATP with sites linked to more than one type of K-channel. This results in the opening of those channels which underlie IKCO (and which are normally inhibited by ATP binding) together with the modulation of phosphorylation-dependent channels such as those which underlie ITO.

The inhibitory effects of cromakalim and its active enantiomer BRL 38227 against various agonists in guinea pig and human airways: comparison with pinacidil and verapamil.[Pubmed:1578358]

J Pharmacol Exp Ther. 1992 May;261(2):429-37.

The effects of the potassium channel activators, cromakalim, BRL 38227 and pinacidil, and the calcium antagonist, verapamil, have been compared against various spasmogens on airway responses in vitro and in vivo in the guinea pig and also in human isolated bronchi. In guinea pig tracheal spirals, potassium channel activators generally had a greater inhibitory effect than verapamil against tone induced by a wide range of spasmogens (spontaneous, 5-hydroxytryptamine, leukotriene D4, prostaglandin E2). The potassium channel activators had very little effect against potassium chloride- and carbachol-induced tone in guinea pig tracheal spirals [e.g., cromakalim (20 microM) induced relaxations of 0.21 +/- 0.03 (relative to an isoprenaline maximum = 1.0, mean +/- S.E.M.) against carbachol, compared to 0.77 +/- 0.03 against histamine]. In vivo, the potassium channel activators prevented histamine and 5-hydroxytryptamine-induced bronchoconstrictions, but had little inhibitory effect against acetylcholine. In contrast, in human bronchi, cromakalim was capable of inducing powerful concentration-dependent relaxations against carbachol-induced tone [cromakalim (20 microM) induced relaxations of 0.77 +/- 0.09 (relative to isoprenaline = 1.0, mean +/- S.E.M.) against carbachol, compared to 0.95 +/- 0.04 against histamine]. In human bronchi, all the inhibitory agents were more potent and more effective, except that verapamil did not have an increased maximum response. We conclude that potassium channel activators should be effective at relaxing contractions induced by a wide range of spasmogens in man.

Synthesis and smooth muscle relaxant activity of a new series of potassium channel activators: 3-amido-1,1-dimethylindan-2-ols.[Pubmed:2002472]

J Med Chem. 1991 Mar;34(3):919-26.

The synthesis of a novel series of smooth muscle relaxants which have been shown to act via the opening or activation of potassium channels is described. Compounds have been evaluated for their ability to inhibit spontaneous tone in guinea pig isolated trachealis and structure-activity relationships are discussed. One compound in particular, 1,1-dimethyl-5-nitro-3-(2-pyridon-1-yl)indan-2-ol, (16) was identified as a potent relaxant of airways smooth muscle in vitro with IC50 = 0.15 microM and was found to significantly inhibit histamine-induced dyspnoea in conscious guinea pigs when given orally 30-45 min prior to challenge.